1. Field of the Invention
The present invention provides the silver salts of phosphanilic acid which are potent antibacterial agents especially against strains of Pseudomonas and thus useful for topical application in the therapy of burns.
2. Description of the Prior Art
Silver sulfadiazine is an antibacterial agent used in the topical treatment of burns. It has disadvantages of sulfonamide sensitivity and the need to monitor sulfonamide concentrations in the bloodstream to prevent renal dysfunction and crystalluria when the burned area covers more than twenty percent of the total body surface. It has also been reported to be effective in the topical treatment of skin ulcers and herpes virus. It is of particular value in burn therapy because of its potent antibacterial activity against infections by strains of Pseudomonas which occur often in such patients.
Silver Sulfadiazine was apparently first disclosed in U.S. Pat. No. 2,422,688 and see also U.S. Pat. Nos. 3,761,590 and 3,792,161. Various complexes are described in U.S. Pat. Nos. 2,536,095 and 2,629,682. Silver derivatives of pyrimidines and purines are disclosed in Farmdoc 69657R. Other preparations and uses are disclosed in Chemical Abstracts, 81, 158672c, Farmdoc 04862X, U.S. Pat. No. 4,020,150, Farmdoc 70776Y and Farmdoc 39520A. For combinations with other, novel metal salts of sulfadiazine, e.g. zinc and cerium, see U.S. Pat. Nos. 4,088,754, 4,078,058 and Farmdoc abstracts 63047Y, 73999X and 04160A.
Silver zinc allantoinate is disclosed in U.S. Pat. No. 3,856,805 as a new compound with bactericidal and wound-healing properties. Silver allantoinate has been described for the treatment of burns in U.K. Pat. No. 1,346,544. See also U.S. Pat. Nos. 3,830,824, 3,830,825 and 3,830,908 which broaden the concept to include other acids and metals such as zinc.
Silver sulfadiazine is marketed as "SILVADENE" Cream by Marion Laboratories Inc., Kansas City, Mo.; see pages 1073-1074 of the 32nd edition of Physicians' Desk Reference published by Medical Economics Company, Oradell, N.J. (1978). Its preparation is described in Farmdoc abstract 39520A. The in vitro antibacterial activity of silver sulfadiazine has been reported, for example, by Carr et al., Antimicrobial Agents and Chemotherapy, 4(5), 585-587 (1973).
Current Science (India), 16, 223-225 (1947) reports the in vitro antibacterial activity of phosphanilic acid and some of its derivatives against E. coli, S. aureus, Typhi murium, C. xerosis and Boyd II.
Current Science (India), 17, 125-6 (1948) reports blood level and toxicity studies with phosphanilic acid in laboratory animals. Their results indicated poor absorption and low toxicity.
H. Bauer, J. Amer. Chem. Soc., 63, 2137-2138 (1941) reported a synthesis of phosphanilic acid as have others such as G. O. Doak et al., J. Amer. Chem. Soc., 74, 753-754 (1952). A few salts are also described in these publications.
J. Pharmacol. Exp. Therap., 74, 163-173 (1942) reports the testing of various sulfonamides, sulfones and related phosphorus compounds against experimental tuberculosis. They found that phosphanilic acid had good tubercularstatic activity in vitro but no effect in vivo, presumably due to low blood concentrations of phosphanilic acid.
Chemical Abstracts, 55, 2883 g (1961) [from Texas Repts. Biol. and Med., 18, 379-394 (1960)] reports that phosphanilic acid had some protective effect when tested in white mice against a standardized infection produced by intravenous injection of the yeast phase of Histoplasma capsulatum.
Antibiotics and Chemotherapy, 3, 256-264 (1953) report the in vitro activity of some aromatic phosphonic and phosphinic acids against a variety of bacterial species. Phosphanilic acid was reported as being generally the most active of the compounds tested. Its activity approached that of sulfathiazole when compared on a molar basis and its antibacterial spectrum was similar to that of sulfanilamide. It was also stated that a later paper would report in detail the findings that phosphanilic acid was effective in vivo in mice infected with S. typhosa, Ps. fluorescens and Plasmodium berghei.
U.S. Pat. No. 3,159,537 discloses the potentiation of various tetracycline antibiotics by admixture with (or salt formation with) various organic oxyphosphorous compounds, including phosphanilic acid.
Ciencia (Mexico), 17, 71-73 (1957) reports studies of the in vitro synergism of mixtures of phosphanilic acid with neomycin or streptomycin on various clinically isolated strains of Salmonella, Shigella and Proteus as well as coliform bacteria capable of inducing fermentation of lactose. The combination of phosphanilic acid and neomycin showed synergism against Salmonella, Proteus and the coliform bacteria. With Shigella, however, there was only slight synergism for low concentrations and only an additive effect, or no effect, at medium and high concentrations.
It was the object of the present invention to provide improved agents for burn therapy which, in addition, lacked the disadvantage of silver sulfadiazine.